January 14, 1997


          Researchers Investigate (Horrors!)
          Nicotine's Potential Benefits

http://www.nytimes.com/yr/mo/day/news/national/nicotine-benefits-sci.h
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          By WARREN E. LEARY

               n work that sounds a little like scientific blasphemy,
               medical researchers have begun paying increasing
               attention to some
          beneficial effects of nicotine that were first noticed in
          cigarette smokers.

          After years of quiet discussion among scientists, hints that
          cigarettes can protect against some diseases or improve the
          outcome of others have led to growing interest in finding
          out why. This has focused attention on nicotine, tobacco's
          most active ingredient, as a potential treatment for several
          major health problems, including Parkinson's and Alzheimer's
          diseases.

          Without question, researchers say, cigarette smoking does
          far more harm than any potential good and should be strongly
          discouraged. Smoking is a major cause of cancer and a host
          of cardiovascular and other diseases that cause millions of
          deaths each year, they say, while draining the world's
          health care systems of billions of dollars.

          But some researchers say efforts to stop smoking have
          discouraged research into the possible benefits of nicotine
          and related compounds in treating conditions like attention
          deficit disorders, an inflammatory bowel disease and a
          neurological condition called Tourette's syndrome.

          "The problem with nicotine is that it is tied to cigarettes
          and therefore seen as 'bad,' " said Dr. Paul Newhouse of the
          University of Vermont College of Medicine. "Clearly, this
          affects getting funding and it makes life difficult for
          those of us interested in nicotine as a drug. A lot of
          people have difficulty in being convinced that nicotine is
          potentially valuable."

          Dr. John A. Baron, a professor of medicine at Dartmouth
          Medical School who has studied the epidemiological link
          between smoking and Parkinson's disease for more than a
          decade, also says there has been resistance to doing
          research on nicotine and possible benefits.

          "The link between smoking and possible benefits is
          uncomfortable for many people," Baron said. "It's hard to
          accept, in an emotional sense, that an exposure so harmful
          in so many ways can have benefit. I detest smoking, but I
          also see evidence that research on nicotine could prove
          valuable and should be done."

          Dr. Zach W. Hall, director of the National Institute of
          Neurological Disorders and Stroke, said the federal
          government spent several million dollars a year on research
          related to nicotine. This work is mainly focused on looking
          at how the chemical acts on the brain and why there are
          receptors in the central nervous system that bind so
          strongly to nicotine, he said.

          "We have supported a program of basic research, which has
          been very fruitful," Hall said. "But we are not currently
          funding research on using nicotine as a treatment."

          Part of the renewed interest in testing nicotine as
          potential therapy for a number of conditions is that the
          chemical has recently become available in numerous
          nontobacco forms that allow it to be readily administered to
          people in different doses without the risks of smoking.
          Nicotine is available to help people stop smoking in
          delivery systems that include patches that allow the
          chemical to be absorbed through the skin, chewing gum, a
          nose spray and an oral inhaler.

          Another advance encouraging nicotine research is a better
          understanding of how the chemical works in the body,
          particularly in the brain. Throughout the body, there are
          protein units called nicotinic cholinergic receptors on the
          surface of many types of cells. Nicotine attaches to the
          receptors and stimulates activity in the cell. In
          particular, it stimulates the release of many types of
          neurotransmitters, chemical messengers that carry signals
          from cell to cell, including dopamine, acetylcholine and
          glutamate.

          Dr. Lorna W. Role, a professor of cell biology and anatomy
          at the Columbia University College of Physicians and
          Surgeons, said work by her group and others showed that
          nicotine binds to brain cells in a way that causes them to
          release a flood of neurotransmitters. This action by
          nicotine amplifies the signals of these neurotransmitters,
          helping to explain the broad spectrum of behavioral and
          cognitive effects that have been attributed to nicotine, she
          said. "This activity primarily affects the limbic system,
          which is the reward center of the brain, which encourages
          people to repeat whatever behavior that stimulated it," she
          said.

          For more than 20 years, evidence has been accumulating that
          cigarette smokers have a reduced risk of developing
          Parkinson's disease. A similar effect has also been noticed
          in epidemiological studies of Alzheimer's disease and
          ulcerative colitis, an inflammatory bowel disease.

          Data from numerous studies, which take into account the
          premature death of some smokers, suggest that smokers have
          half the risk of developing Parkinson's disease as those who
          have never smoked, researchers say, and several small
          studies have indicated that there is also a reduced risk for
          Alzheimer's disease, particularly with the inherited form of
          the disease.

          Parkinson's disease, a degenerative brain condition that
          results in tremors and loss of body control, is
          characterized by the death of brain cells that make the
          neurotransmitter dopamine and can be treated with drugs that
          replace the chemical.

          "Nicotine stimulates dopamine production in the brain and
          this could be a reason smoking appears to be beneficial with
          Parkinson's," said Dr. Newhouse of the University of
          Vermont. There are preliminary indications from small
          studies that nicotine patches or intravenous infusions of
          nicotine may help treat Parkinson's symptoms, he said.

          The relationship between nicotine and Alzheimer's disease, a
          progressive brain condition that leads to dementia and loss
          of memory, is also spurring interest. Dr. Michael G.
          Zagorski and his colleagues at Case Western Reserve
          University have found that nicotine appears to interfere
          with a major process of Alzheimer's, the formation of beta
          amyloid plaque deposits that block cell-to-cell
          communication. The researchers found in test-tube studies
          that nicotine kept soluble, beta-peptide chemicals from
          transforming into plaques that are toxic to nerve cells.

          Zagorski said the finding might help explain the inverse
          relationship between smoking and Alzheimer's that had been
          shown in epidemiological studies, and could lead to
          development of nicotine-like compounds that prevented or
          slowed the formation of amyloid plaque.

          Researchers are also developing artificial compounds that
          are either structurally or functionally similar to nicotine,
          hoping to mimic the action of the chemical without some of
          its side effects.

          Animal and human studies have shown that nicotine can
          enhance learning, memory, cerebral blood flow and the
          performance of certain repetitive tasks. Researchers have
          developed a series of nicotine-like compounds to enhance
          certain effects to make them more useful for particular
          diseases while reducing unwanted side effects.

          Newhouse recently reported on a small study he conducted
          with Alzheimer's patients using a nicotine analogue
          developed by Abbott Laboratories called ABT-418. After
          six-hour infusions with the drug, researchers found
          significant increases in short-term recall, improvements in
          spatial memory and better reaction times on tests.

          Dr. G. Kenneth Lloyd of Sibia Neurosciences Inc. in San
          Diego said his company was testing two nicotine-like
          compounds that separately targeted Parkinson's and
          Alzheimer's diseases. The idea is to home in on certain
          types of nicotine receptors in the brain, he said.

          One compound, SIB 1508Y, works on the release of the
          neurotransmitters dopamine and acetylcholine to target
          cognitive dysfunction associated with Parkinson's disease,
          and the other, SIB 1553A, enhances release of acetylcholine
          in hope of reversing short- and long-term memory defects
          associated with aging and Alzheimer's disease, Lloyd said.

          The company announced last month that based on promising
          results with animals, it had applied with the Food and Drug
          Administration to begin preliminary safety and dosage tests
          of SIB 1508Y in humans.

          Researchers have long noticed that ulcerative colitis, a
          chronic inflammation of the colon and rectum, is mostly a
          disease of nonsmokers.

          In a randomized, controlled trial with 72 patients,
          researchers at University Hospital of Wales in Cardiff found
          that after six weeks of using nicotine patches, patients had
          significantly improved symptoms.

          Digestive disease specialists note, however, that smoking
          and nicotine apparently have the opposite effect on a
          related inflammatory bowel condition, Crohn's disease.
          Studies indicate that smoking increases the risk and
          severity of Crohn's.

          Dr. Edward D. Levin of Duke University Medical Center
          studied the effects of nicotine patches on schizophrenic
          patients who were given haloperidol, a commonly used
          treatment but one with side effects harmful to memory and
          alertness. He found that nicotine significantly reduced the
          memory impairment caused by haloperidol.

          Dr. Paul R. Sanberg, a professor of neurological surgery at
          the University of South Florida in Tampa, has tested
          nicotine patches and haloperidol on patients with Tourette's
          syndrome, which causes them to twitch constantly and mutter
          meaningless sounds or phrases.

          Sanberg said the nicotine patch helped patients on whom
          haloperidol did not work well. He was co-author of a letter
          published in the journal Nature in October saying there was
          growing evidence indicating that nicotine had therapeutic
          properties.


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